Non insulin dependent diabetes mellitus (NIDDM or Type II) is the fourth-leading cause of death in the United States and affects from 5 to 7% of the total world population, with an increasing prevalence in western countries. In diabetes, the body either does not produce enough insulin or the insulin which is produced is not effective, resulting in increased blood glucose level, a condition technically known as hyperglycemia. Although diabetes can affect people of any age, the majority of diabetics are over 45 years old. The disease tends to run in families, and the risk factor of acquiring the disease increases in overweight individuals.
Diabetes is a chronic disease with no cure and is linked with several other disorders. It is the leading cause of blindness in people ages 25-74. Ten percent of all people with diabetes develop kidney disease. Diabetes is the most frequent cause of non-traumatic lower limb amputation. The risk of leg amputation is 30 times greater for people with diabetes. People with diabetes are two to four times more likely to develop heart diseases, and are five times more likely to suffer from stroke.
The cause of diabetes is still a mystery, although both genetics and environment appear to play a role. There are two types of diabetes: Insulin dependent (Type I) and Non-insulin dependent (Type II). Type I diabetes is an autoimmune disease frequently occurring in children and young adults. The autoantigen responsible for triggering Type I diabetes is still unknown and patients have to take i.v. insulin daily to survive for their life.
Type II diabetes is a metabolic disorder resulting from the body's inability to make a sufficient amount of insulin or to properly use the insulin that it does produce, and is considered the most common form of the disease. Although insulin secretion and insulin resistance are considered the major defects, the precise genetic factors involved remain unknown. Patients with diabetes usually have one or more of the following defects. These are: less production of insulin by the pancreas; oversecretion of glucose by the liver; impairment of glucose uptake by the skeletal muscle; defects in glucose transporters (Glut-1, Glut-4); desensitization of insulin receptors; and defect in the metabolic breakdown of polysaccharides.
The current therapy utilizes four classes of oral hypoglycemic agents besides i.v. insulin. These are summarized below:
______________________________________ Approved Mechanisms Class Drugs of Action Limitations ______________________________________ Sulfonylureas 4 (1st gen.) Acts on pancreas to Resistance 2 (2nd gen.) release more insulin development Biguanides Only one Reduces glucose Liver problem (metformin) secretion by liver. Lactic Also improves acidosis insulin sensitivity. .alpha.-Glucosidase Only one Interferes with Only at Inhibitor (acarbose) digestive process. postprandial Reduces glucose level. absorption. Thiazolidine Only one Reduces insulin "Add-on" dione (troglitazone) resistency with insulin Not for people with heart and liver disease. ______________________________________
As is apparent from the above table, each of the current agents available for use in the treatment of diabetes has certain disadvantages. Accordingly there is continued interest in the identification and development of new agents for use in the treatment of diabetes.
M.charantia is a tropical plant whose fruits are used as a vegetable. Several groups have reported on the hypoglycemic activity of M.charantia, both in mammal models (Shibib et al., Biochem. J., 292, 267-270 (1993); Ali et al., Planta Med. 59, 408-412 (1993); Akhtar et al., Planta Med. 42, 205-212 (1981)) and in humans (Leatherdale et al., Br. Med. J. 282, 1823-1824 (1981); Aslam et al., Lancet, I. 607 (1979)). However, the hypoglycemic component and the mechanism of action remains unknown.
The isolation of an 11 kDal peptide obtained from M.charantia having insulin like activity is reported in: Khanna et al., "Hypoglycemic Activity of Polypeptide-p from a Plant Source," 20th Annual Meeting of the American Society of Pharmacology, Purdue University, West Lafayette, Jul. 29-Aug. 3, 1979; Baldwa et al., Upsala J. Med. Sci. (1977) 82:39-41 and U.S. Pat. No. 3,945,988. In all of these reports, the insulin like polypeptide was non-orally administered, e.g. i.v. or subcutaneously.
A recent report indicates that the crude alcoholic extract of M.charantia lowers plasma glucose level partly by stimulation of glycogen synthesis in the liver and it is unlikely that it acts as an insulin secreting agent (Sarkar et al., Pharmacol. Res., 33, 1-4 (1996)).